The opioid crisis has taken over half a million lives in the U.S. since 1999, with about 75% of those being male, as reported by the National Institutes of Health (NIH). While the higher rates of opioid misuse and overdose fatalities among men are well-recorded, the reasons for this gender gap remain unclear.
A recent investigation conducted on rats by researchers at Washington University School of Medicine in St. Louis proposes that a biological factor may be a fundamental cause. Male rats experiencing chronic pain administered progressively larger doses of an opioid — specifically, fentanyl — over time, whereas female rats with the identical pain condition maintained a consistent intake level, akin to observed human behavior. The researchers identified that this behavioral variation was influenced by sex hormones: administering estrogen to male rats resulted in a stable level of fentanyl consumption.
The results, published on March 10 in the journal Neuron, suggest that the distinctions in opioid usage and misuse between men and women might be hormonal in nature and that a more profound comprehension of how sex hormones engage with chronic pain could lead to innovative strategies for tackling the opioid crisis.
“These findings propose that males may have an inherent propensity to misuse opioids in the backdrop of pain due to their hormonal balance,” stated the lead author Jessica Higginbotham, a postdoctoral researcher in the lab of Jose Moron-Concepcion, the Henry Elliot Mallinckrodt Professor of Anesthesiology at WashU Medicine and the study’s senior author. “We concentrated on estrogen in this research, but I suspect that the phenomenon we observed is not attributed solely to estrogen. It is more plausible that the overall balance of all sex hormones in the body impacts risk. Males and females possess the same sex hormones, just in varying quantities, and our findings suggest that females have a more protective hormonal equilibrium compared to males. However, if that equilibrium shifts, the likelihood of developing opioid use disorder could also change.”
Impact of pain on opioid-induced pleasure
Most individuals who misuse opioids do so to alleviate pain, yet men are more likely to experience overdose than women, even though they generally endure less chronic pain, according to national survey data. Researchers speculate that factors beyond, or in addition to, chronic pain may be contributing to the elevated addiction risks among men.
When an individual — whether human or rat — consumes an opioid like fentanyl, it affects the brain in two primary ways. The substance inhibits the transmission of pain signals, easing discomfort, and stimulates the release of dopamine from the brain’s reward center, inducing feelings of pleasure. Prior research by Moron-Concepcion and his team indicated that pain itself influences dopamine levels in the brain, signifying potential interactions between opioids and pain that could alter dopamine signaling.
To delve into how pain impacts opioid-seeking behaviors distinctly by sex, Higginbotham and Moron-Concepcion examined rats suffering from chronic pain in their paws. They discovered no notable differences between genders regarding the severity of pain experienced, as indicated by the speed at which the animals withdrew their paws when touched. They also noted no variations between male and female rats in terms of the pain relief afforded by fentanyl doses. Despite this, the male rats continued to seek fentanyl increasingly throughout the three-week study, whereas female rats did not.
The researchers identified a crucial disparity between male and female rats concerning the quantity of dopamine released following a fentanyl dose. Female rats consistently produced the same amount of dopamine in response to fentanyl, irrespective of their pain status. Males not in pain exhibited responses akin to females. Conversely, males enduring chronic pain displayed progressively augmented dopamine responses to fentanyl over time. In essence, while pain amplified the euphoric effects of opioids for males, no similar response was seen in females.
“We initially believed that males might have developed a tolerance to fentanyl, necessitating larger amounts to alleviate pain, but that was not the case,” stated Moron-Concepcion, who also serves as a professor of psychiatry and neuroscience. “The males sought increased amounts of fentanyl primarily to achieve a heightened sense of euphoria. In males, unlike females, the pain condition itself influenced the reward circuits within the brain, prompting them to consume more substances.”
Estrogen curtails fentanyl consumption
Additional experiments revealed that sex hormones were to blame for the divergent dopamine responses observed in male and female rats.
Ovaries function as the main source of sex hormones in females, generating estrogen, progesterone, and minor quantities of testosterone. The researchers determined that female rats whose ovaries had been excised exhibited responses to fentanyl similar to males, marked by increased dopamine release and heightened opioid-seeking behavior. In contrast, male rats administered estrogen exhibited dopamine responses and opioid-seeking behaviors comparable to those of females. These results imply that a decline in estrogen levels during menopause may help elucidate the higher rates of opioid abuse in older women compared to their younger counterparts, Higginbotham noted.
“What we can pursue now is exploring ways to achieve the optimal hormonal balance to avert opioid use disorder in individuals suffering from chronic pain,” Moron-Concepcion stated. “We have yet to investigate the contributions of other sex hormones such as testosterone or progesterone. Is there an ideal combination of hormones that can mitigate the effects of pain on opioid usage? That’s a question we aim to explore.”
Higginbotham JA, Abt JG, Teich RH, Dearman JJ, Lintz T, Morón JA. Estradiol safeguards against pain-facilitated fentanyl consumption via suppression of opioid-induced dopamine activity in males. Neuron. March 10, 2025. DOI: 10.1016/j.neuron.2025.02.013
This research was funded by the National Institutes of Health (NIH), grant numbers DA726129, DA041781, DA042581, DA042499, DA041883, and DA045463; a W. M. Keck Fellowship; and the Brain and Behavior Research Foundation, NARSAD Independent Investigator Award. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the NIH.
About Washington University School of Medicine
WashU Medicine is a prominent institution in academic medicine, specializing in biomedical research, patient care, and educational endeavors, supported by 2,900 faculty members. Its National Institutes of Health (NIH) research funding portfolio ranks second among U.S. medical schools and has expanded by 56% over the past seven years. Together with institutional investments, WashU Medicine commits over $1 billion each year to both fundamental and clinical research innovation and training. Its faculty practice consistently ranks within the top five nationally, comprising over 1,900 faculty physicians practicing across 130 locations, who also serve as the medical staff for Barnes-Jewish and St. Louis Children’s hospitals under BJC HealthCare. WashU Medicine has a distinguished history in MD/PhD education, recently allocating $100 million to scholarships and curriculum enhancements for its medical students, and is home to exemplary training programs across all medical subspecialties, in addition to physical therapy, occupational therapy, and audiology and communication sciences.
Originally published on the WashU Medicine website
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